Differential natural killer cell–mediated inhibition of HIV-1 replication based on distinct KIR/HLA subtypes

Decline of peak viremia during acute HIV-1 infection occurs before the development of vigorous adaptive immunity, and the level of decline correlates inversely with the rate of AIDS progression, implicating a potential role for the innate immune response in determining disease outcome. The combined expression of an activating natural killer (NK) cell receptor, the killer immunoglobulin-like receptor (KIR) 3DS1, and its presumed ligand, human leukocyte antigen (HLA)–B Bw4-80I, has been associated in epidemiological studies with a slow progression to AIDS. We examined the functional ability of NK cells to differentially control HIV-1 replication in vitro based on their KIR and HLA types. NK cells expressing KIR3DS1 showed strong, significant dose- and cell contact–dependent inhibition of HIV-1 replication in target cells expressing HLA-B Bw4-80I compared with NK cells that did not express KIR3DS1. Furthermore, KIR3DS1+ NK cells and NKLs were preferentially activated, and lysed HIV-1 infected target cells in an HLA-B Bw4-80I–dependent manner. These data provide the first functional evidence that variation at the KIR locus influences the effectiveness of NK cell activity in the containment of viral replication.

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Slaying the Trojan Horse: Natural Killer Cells Exhibit Robust Anti-HIV-1 Antibody-Dependent Activation and Cytolysis against Allogeneic T Cells

Journal of Virology ◽

10.1128/jvi.02461-14 ◽

2014 ◽

Vol 89 (1) ◽

pp. 97-109 ◽

Cited By ~ 31

Author(s):

Shayarana L. Gooneratne ◽

Jonathan Richard ◽

Wen Shi Lee ◽

Andrés Finzi ◽

Stephen J. Kent ◽

...

Keyword(s):

T Cells ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Target Cells ◽

Dependent Manner ◽

Inhibitory Receptors ◽

Cell Responses ◽

Anti Hiv ◽

Hiv 1

ABSTRACTMany attempts to design prophylactic human immunodeficiency virus type 1 (HIV-1) vaccines have focused on the induction of neutralizing antibodies (Abs) that block infection by free virions. Despite the focus on viral particles, virus-infected cells, which can be found within mucosal secretions, are more infectious than free virus bothin vitroandin vivo. Furthermore, assessment of human transmission couples suggests infected seminal lymphocytes might be responsible for a proportion of HIV-1 transmissions. Although vaccines that induce neutralizing Abs are sought, only some broadly neutralizing Abs efficiently block cell-to-cell transmission of HIV-1. As HIV-1 vaccines need to elicit immune responses capable of controlling both free and cell-associated virus, we evaluated the potential of natural killer (NK) cells to respond in an Ab-dependent manner to allogeneic T cells bearing HIV-1 antigens. This study presents data measuring Ab-dependent anti-HIV-1 NK cell responses to primary and transformed allogeneic T-cell targets. We found that NK cells are robustly activated in an anti-HIV-1 Ab-dependent manner against allogeneic targets and that tested target cells are subject to Ab-dependent cytolysis. Furthermore, the educated KIR3DL1+NK cell subset from HLA-Bw4+individuals exhibits an activation advantage over the KIR3DL1−subset that contains both NK cells educated through other receptor/ligand combinations and uneducated NK cells. These results are intriguing and important for understanding the regulation of Ab-dependent NK cell responses and are potentially valuable for designing Ab-dependent therapies and/or vaccines.IMPORTANCENK cell-mediated anti-HIV-1 antibody-dependent functions have been associated with protection from infection and disease progression; however, their role in protecting from infection with allogeneic cells infected with HIV-1 is unknown. We found that HIV-1-specific ADCC antibodies bound to allogeneic cells infected with HIV-1 or coated with HIV-1 gp120 were capable of activating NK cells and/or trigging cytolysis of the allogeneic target cells. This suggests ADCC may be able to assist in preventing infection with cell-associated HIV-1. In order to fully utilize NK cell-mediated Ab-dependent effector functions, it might also be important that educated NK cells, which hold the highest activation potential, can become activated against targets bearing HIV-1 antigens and expressing the ligands for self-inhibitory receptors. Here, we show that with Ab-dependent stimulation, NK cells expressing inhibitory receptors can mediate robust activation against targets expressing the ligands for those receptors.

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IL-17 constrains natural killer cell activity by restraining IL-15–driven cell maturation via SOCS3

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1904125116 ◽

2019 ◽

Vol 116 (35) ◽

pp. 17409-17418 ◽

Cited By ~ 4

Author(s):

Xuefu Wang ◽

Rui Sun ◽

Xiaolei Hao ◽

Zhe-Xiong Lian ◽

Haiming Wei ◽

...

Keyword(s):

Antiviral Activity ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Natural Killer Cell Activity ◽

Killer Cell ◽

Cell Activity ◽

Cell Maturation ◽

Dependent Manner ◽

Deficient Mice

Increasing evidence demonstrates that IL-17A promotes tumorigenesis, metastasis, and viral infection. Natural killer (NK) cells are critical for defending against tumors and infections. However, the roles and mechanisms of IL-17A in regulating NK cell activity remain elusive. Herein, our study demonstrated that IL-17A constrained NK cell antitumor and antiviral activity by restraining NK cell maturation. It was observed that the development and metastasis of tumors were suppressed in IL-17A–deficient mice in the NK cell-dependent manner. In addition, the antiviral activity of NK cells was also improved in IL-17A–deficient mice. Mechanistically, ablation of IL-17A signaling promoted generation of terminally mature CD27−CD11b+ NK cells, whereas constitutive IL-17A signaling reduced terminally mature NK cells. Parabiosis or mixed bone marrow chimeras from Il17a−/−and wild-type (WT) mice could inhibit excessive generation of terminally mature NK cells induced by IL-17A deficiency. Furthermore, IL-17A desensitized NK cell responses to IL-15 and suppressed IL-15–induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) via up-regulation of SOCS3, leading to down-regulation of Blimp-1. Therefore, IL-17A acts as the checkpoint during NK cell terminal maturation, which highlights potential interventions to defend against tumors and viral infections.

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Monocytes control natural killer cell differentiation to effector phenotypes

Blood ◽

10.1182/blood-2010-10-312264 ◽

2011 ◽

Vol 117 (17) ◽

pp. 4511-4518 ◽

Cited By ~ 59

Author(s):

Katrina Soderquest ◽

Nick Powell ◽

Carmelo Luci ◽

Nico van Rooijen ◽

Andrés Hidalgo ◽

...

Keyword(s):

Cell Differentiation ◽

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

In Vivo Model ◽

Dependent Manner ◽

Nk Cell Differentiation

Abstract Natural killer (NK) cells play a major role in immunologic surveillance of cancer. Whether NK-cell subsets have specific roles during antitumor responses and what the signals are that drive their terminal maturation remain unclear. Using an in vivo model of tumor immunity, we show here that CD11bhiCD27low NK cells migrate to the tumor site to reject major histocompatibility complex class I negative tumors, a response that is severely impaired in Txb21−/− mice. The phenotypical analysis of Txb21-deficient mice shows that, in the absence of Txb21, NK-cell differentiation is arrested specifically at the CD11bhiCD27hi stage, resulting in the complete absence of terminally differentiated CD11bhiCD27low NK cells. Adoptive transfer experiments and radiation bone marrow chimera reveal that a Txb21+/+ environment rescues the CD11bhiCD27hi to CD11bhiCD27low transition of Txb21−/− NK cells. Furthermore, in vivo depletion of myeloid cells and in vitro coculture experiments demonstrate that spleen monocytes mediate the terminal differentiation of peripheral NK cells in a Txb21- and IL-15Rα–dependent manner. Together, these data reveal a novel, unrecognized role for Txb21 expression in monocytes in promoting NK-cell development and help appreciate how various NK-cell subsets are generated and participate in antitumor immunity.

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Patients with a deficiency of natural killer cell activity lack the VEP13-positive lymphocyte subpopulation

Blood ◽

10.1182/blood.v65.1.65.bloodjournal65165 ◽

1985 ◽

Vol 65 (1) ◽

pp. 65-70 ◽

Cited By ~ 1

Author(s):

HW Ziegler-Heitbrock ◽

H Rumpold ◽

D Kraft ◽

C Wagenpfeil ◽

R Munker ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Natural Killer Cell Activity ◽

Killer Cell ◽

Cell Activity ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Target Cells ◽

Nk Cell Activity

Many patients with B-type chronic lymphocytic leukemia (CLL) exhibit a profound defect in their natural killer (NK) cell activity, the basis of which is still obscure. Hence, we analyzed the NK cells from peripheral blood samples from 11 patients with CLL for phenotype and function, after removal of the leukemic cells with a monoclonal antibody (BA-1) plus complement. Phenotypic analysis of these nonleukemic cells with monoclonal antibodies (MoAbs) against NK cells revealed that the CLL patients had higher percentages of HNK-1-positive cells (23.5% compared to controls with 14.7%). In contrast, VEP13- positive cells were absent or low in seven patients (0.8% compared to controls with 11.2%) and normal in four patients (10.5%). When testing NK cell activities against K562 or MOLT 4 target cells, patients with no or minimal numbers of VEP13-positive cells were found to be deficient, while patients with normal percentages of VEP13-positive cells had NK cell activity comparable to controls. Isolation by fluorescence-activated cell sorter of HNK-1-positive cells from patients lacking VEP13-positive cells and NK cell activity indicated that the majority of the HNK-1-positive cells in these patients had the large granular lymphocyte morphology that is characteristic of NK cells. Thus, the deficiency of NK cell activity in CLL patients appears to result from the absence of cells carrying the VEP13 marker.

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Effects of Emitted Qi on In Vitro Natural Killer Cell Cytotoxic Activity

The American Journal of Chinese Medicine ◽

10.1142/s0192415x01000034 ◽

2001 ◽

Vol 29 (01) ◽

pp. 17-22 ◽

Cited By ~ 19

Author(s):

Myeong Soo Lee ◽

Hwa Jeong Huh ◽

Hye-Sook Jang ◽

Chang Sub Han ◽

Hoon Ryu ◽

...

Keyword(s):

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

Cell Activity ◽

K562 Cells ◽

Target Cells ◽

Cell Cytotoxicity ◽

Nk Cell Activity ◽

Nk Cell Cytotoxicity

The present study investigated the effects of Korean Qi-therapy, ChunSoo Energy Healing, on natural killer (NK) cell cytotoxicity in vitro depending on Qi-treatment time and the types of cells treated. NK cell cytotoxicity was assayed by measuring LDH release from tumor target cells (K562 cell lines). NK activity was significantly increased by emitted-Qi treatment of 30 sec duration. Three and 5 minutes of Qi projection created the greatest increase in NK cell activity when mixtures of NK cells and K562 cells were treated (1.81 and 2.12 fold for 4 hr culture; 1.54 and 1.36 for 16 hr culture, respectively). NK cell activity increased significantly in Qi-treated K562 cells alone (1.13 fold, p < 0.05) compared to control. These results are consistent with in vivo Qi-therapy on humans and suggests that emitted-Qi has an acute stimulatory effect on NK cell activity. This study provides direct scientific support that Qi as such may positively affect human cellular immunity.

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Identification of Primary Natural Killer Cell Modulators by Chemical Library Screening with a Luciferase-Based Functional Assay

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/2472555218797078 ◽

2018 ◽

Vol 24 (1) ◽

pp. 25-37 ◽

Cited By ~ 1

Author(s):

Simon Hayek ◽

Nassima Bekaddour ◽

Laurie Besson ◽

Rodolphe Alves de Sousa ◽

Nicolas Pietrancosta ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Killer Cell ◽

Cell Activity ◽

Target Cells ◽

Functional Assay ◽

Functional Screening ◽

Cell Functions ◽

Ifn Γ

Natural killer (NK) cells are essential players of the innate immune response that secrete cytolytic factors and cytokines such as IFN-γ when contacting virus-infected or tumor cells. They represent prime targets in immunotherapy as defects in NK cell functions are hallmarks of many pathological conditions, such as cancer and chronic infections. The functional screening of chemical libraries or biologics would greatly help identify new modulators of NK cell activity, but commonly used methods such as flow cytometry are not easily scalable to high-throughput settings. Here we describe an efficient assay to measure the natural cytotoxicity of primary NK cells where the bioluminescent enzyme NanoLuc is constitutively expressed in the cytoplasm of target cells and is released in co-culture supernatants when lysis occurs. We fully characterized this assay using either purified NK cells or total peripheral blood mononuclear cells (PBMCs), including some patient samples, as effector cells. A pilot screen was also performed on a library of 782 metabolites, xenobiotics, and common drugs, which identified dextrometorphan and diphenhydramine as novel NK cell inhibitors. Finally, this assay was further improved by developing a dual-reporter cell line to simultaneously measure NK cell cytotoxicity and IFN-γ secretion in a single well, extending the potential of this system.

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The role of cytokine in regulation of the natural killer cell activity

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh0808423j ◽

2008 ◽

Vol 136 (7-8) ◽

pp. 423-429 ◽

Cited By ~ 5

Author(s):

Vladimir Jurisic ◽

Sladjana Stojacic-Djenic ◽

Natasa Colovic ◽

Gordana Konjevic

Keyword(s):

Immune System ◽

Nk Cells ◽

Natural Killer ◽

Cell Function ◽

Nk Cell ◽

Natural Killer Cell Activity ◽

Killer Cell ◽

Cell Activity ◽

Target Cells

Natural killer (NK) cells are characterized by a CD3-CD16+ CD56+ immunophenotype and have a central role in the innate immune system. They are defined by their capacity to kill certain tumor-target cells or virus infected cells without prior sensitization or MHC-restriction. The activity of the NK cells is determined by the balance between activation and inhibitory receptor molecules expressed on the surface of NK cells. However, several cytokines and chemokines can significantly modulate their activity, inducing increase of NK cell activity. Immunomodulation mediated by NK cells is very important mechanism in tumor immunity, as well as in other immunodepressions of the immune system. In this study, we summarize the role of several cytokines, including IFN, IL-1, IL-2, IL-4, IL-7, IL-12 and IL-17, on NK cell function. The NK cells, after activation, depending on cytokine environment, can differentiate into NK1 cells that produce Th1 cytokine type (IFN-?, IL-2, IL-12) or NK2 cells that produce Th2 type cytokines, enhance exocytosis and release of previously formed molecules from NK cells (granzyme, perforin). We also describe that the release of cytokines and mediators show local or distance effects, or induce apoptosis (mostly by secreted TNF-?) after binding appropriated killer cell receptors from TNF receptor superfamily.

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Inhibition of the αv integrin-TGF-β axis improves natural killer cell function against glioblastoma stem cells

10.1101/2020.03.30.016667 ◽

2020 ◽

Cited By ~ 1

Author(s):

Hila Shaim ◽

Mayra Hernandez Sanabria ◽

Rafet Basar ◽

Fang Wang ◽

May Daher ◽

...

Keyword(s):

Stem Cells ◽

Nk Cells ◽

Single Cell ◽

Natural Killer ◽

Cell Function ◽

Nk Cell ◽

Killer Cell ◽

Cell Contact ◽

Glioblastoma Stem Cells

ABSTRACTGlioblastoma, the most aggressive brain cancer, often recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. Here, we show that patient-derived GSCs, but not normal astrocytes, are highly sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. In contrast, single cell analysis of autologous, tissue infiltrating NK cells isolated from surgical samples of high-grade glioblastoma patient tumors using mass cytometry and single cell RNA sequencing revealed an abnormal phenotype associated with impaired lytic function compared with peripheral blood NK cells from GBM patients or healthy donors. This immunosuppression was attributed to an integrin-TGF-β mechanism, activated by direct cell-cell contact between GSCs and NK cells. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling, or with TGF-β receptor 2 gene-edited NK cells prevented GSC-induced NK cell dysfunction and tumor growth. Collectively, our findings reveal a novel mechanism of NK cell immune evasion by GSCs and implicate the integrin-TGF-β axis as a useful therapeutic target to eliminate GSCs in this devastating tumor.

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Patients with a deficiency of natural killer cell activity lack the VEP13-positive lymphocyte subpopulation

Blood ◽

10.1182/blood.v65.1.65.65 ◽

1985 ◽

Vol 65 (1) ◽

pp. 65-70 ◽

Cited By ~ 12

Author(s):

HW Ziegler-Heitbrock ◽

H Rumpold ◽

D Kraft ◽

C Wagenpfeil ◽

R Munker ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Natural Killer Cell Activity ◽

Killer Cell ◽

Cell Activity ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Target Cells ◽

Nk Cell Activity

Abstract Many patients with B-type chronic lymphocytic leukemia (CLL) exhibit a profound defect in their natural killer (NK) cell activity, the basis of which is still obscure. Hence, we analyzed the NK cells from peripheral blood samples from 11 patients with CLL for phenotype and function, after removal of the leukemic cells with a monoclonal antibody (BA-1) plus complement. Phenotypic analysis of these nonleukemic cells with monoclonal antibodies (MoAbs) against NK cells revealed that the CLL patients had higher percentages of HNK-1-positive cells (23.5% compared to controls with 14.7%). In contrast, VEP13- positive cells were absent or low in seven patients (0.8% compared to controls with 11.2%) and normal in four patients (10.5%). When testing NK cell activities against K562 or MOLT 4 target cells, patients with no or minimal numbers of VEP13-positive cells were found to be deficient, while patients with normal percentages of VEP13-positive cells had NK cell activity comparable to controls. Isolation by fluorescence-activated cell sorter of HNK-1-positive cells from patients lacking VEP13-positive cells and NK cell activity indicated that the majority of the HNK-1-positive cells in these patients had the large granular lymphocyte morphology that is characteristic of NK cells. Thus, the deficiency of NK cell activity in CLL patients appears to result from the absence of cells carrying the VEP13 marker.

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WF10 Stimulates NK Cell Cytotoxicity by Increasing LFA-1-Mediated Adhesion to Tumor Cells

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/436587 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Louisa Kühne ◽

Mathias Konstandin ◽

Yvonne Samstag ◽

Stefan Meuer ◽

Thomas Giese ◽

...

Keyword(s):

Nk Cells ◽

Cell Activation ◽

Nk Cell ◽

Killer Cell ◽

Target Cells ◽

Dependent Manner ◽

Cell Cytotoxicity ◽

Natural Killer Cell Cytotoxicity ◽

Nk Cell Cytotoxicity

The redox-active chlorite-based drug WF10 (Immunokine) was shown to have modulatory effects on both the innate and adaptive immune systemin vitroandin vivo. Animal studies suggest that WF10 enhances immunity against tumors. One possible explanation for such an effect is that WF10 stimulates natural killer cell cytotoxicity against malignant cells. Here, we show that WF10 regulates human NK cell cytotoxicity in a time-dependent manner, following an S-shaped kinetic with an initial stimulation of activity followed by a decrease in activity relative to the untreated controls. WF10 does not activate NK cells on its own but co-stimulates NK cell activation mediated by different activating receptors. This is mediated by enhancing NK cell adhesion to target cells through promoting the activation of the integrin LFA-1. These data demonstrate a direct effect of WF10 on the cytotoxicity of human NK cells.

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